Methods of Inducing Cellular Damage are Rarely Relevant to Aging, and the Details Matter

One of the major challenges in aging research is determining whether or not models of cellular or organismal damage and its consequences are in any way relevant to the natural processes of aging. One can hit a brick with a hammer, but that says very little about how bricks weather over the years. One can hit the brick very carefully with the hammer in ways that produce results that look weathering-like, but can that be used to tell us anything about weathering? In cells the line between artificial and natural damage can be hard to pin down, but the fine details of the processes involved always matter. It is easy to break cells and see them become dysfunctional as a result, but hard to determine the relevance of that breakage to natural aging. Even in the example here, in which researchers are trying to achieve something very similar to the consequences of excessive oxidative damage in mitochondria that is observed in aging, it is possible to argue that the methodology used has little relevance to the actual damage of aging in its details, and therefore may not be a useful model.

Researchers have carried out a causal experiment to kick off a mitochondrial chain reaction that wreaks havoc on the cell, all the way down to the genetic level. "I like to call it 'the Chernobyl effect' - you've turned the reactor on and now you can't turn it off. You have this clean-burning machine that's now polluting like mad, and that pollution feeds back and hurts electron transport function. It's a vicious cycle." The researchers used a new technology that produces damaging reactive oxygen species - in this case, singlet oxygen - inside the mitochondria when exposed to light. "That's the Chernobyl incident. Once you turn the light off, there's no more singlet oxygen anymore, but you've disrupted the electron transport chain, so after 48 hours, the mitochondria are still leaking out reactive oxygen - but the cells aren't dying, they're just sitting there erupting."

At this point, the nucleus of the cell is being pummeled by free radicals. It shrinks and contorts. The cell stops dividing. Yet, the DNA seems oddly intact. That is, until the researchers start looking specifically at the telomeres - the protective caps on the end of each chromosome that allow them to continue replicating and replenishing. Telomeres are extremely small, so DNA damage restricted to telomeres alone may not show up in a whole-genome test, like the one the researchers had been using up to this point. So, to see the genetic effects of the mitochondrial meltdown, the researchers had to light up those tiny endcaps with fluorescent tags, and lo and behold, they found clear signs of telomere fragility and breakage. Then, in a critical step, the researchers repeated the whole experiment on cells with inactivated mitochondria. Without the mitochondria to perpetuate the reaction, there was no buildup of free radicals inside the cell and no telomere damage.

Link: https://www.upmc.com/media/news/082619-pnas-van-houten

Comments

So could I get some other peoples opinion about the ROS theory of aging as "ROS are a 'significant' contributor in causing cellular senescence through a multitude of already studies mechanisms"...

If these is even remotely true wouldn't getting active concentrations of antioxidants in the blood stream and measured in tissue help mitigate these effects?

Yes this may be hard to study and prove but in theory/ big picture?

(and yes i understand hormesis and how too much supplementation can be a bad thing and throw off the bodies natural antioxidant expression up regulation upon instults due to excessive supplementation, but this remains to be proven?)

Posted by: Steven at August 29th, 2019 10:48 AM

Hi Steven! Just a 2 cents.

This study is interesting (and, lately, there aren't that many anymore, that's because we touched the bottom of the barrel (the biolitterature is packed at the seams); there isn't all much more to uncover (things stalling/repeating themselves; like more CR studies...really? it's done to death) and why studies now are more dull, 2010-2018 are truly the best years (the years of comparative biogerontology in animals), also I guess scientists are starting to tackle aging (do something about it/stop it) getting busy, rather than just observe it/classify it/make more 'research data' for 'research data'/vapor (and no action on it), just informative/passive; not (re)active - ...like the ROS (reactive oxygen species); if only they behaved more like them, minus their volatility))).

Yes, it is (at the least) remotely true; even more than remotely, but closely/most likely true.

Yes, antioxidants do that and will, most likely, slow telomere attrition - as long as they remain ANTIoxidants, because some don't (they turn pro-oxidants, depending on various factors...it is that 'thin walking-line'..as you said...too much of a good thing is just as bad as too little. My grand-mother used to say: ''if you eat oranges equalling the size of a truck's cargo....you will die''.
She was on to Something, it'S not because it's a fruit or it has citric/citrus/xanthyne polyphenols that these antioxidants from it's peels and content will 'save you'; especially, if you eat a truck full of them. I know, I ate them (en masse) and still had atherosclerosis. Antioxidants only, briefly, assuage things; they do not reverse things, rather they contribute to the possibility of restoring homeostasis: redox ((red)uction:(ox)idation), the balance between oxidation and antioxidation; there is one, and the redox is behind it. In aging, hormesis is just 'priming' the body and forcing it to activate stress-countering mechanisms; so it's a 'response', but only a 'dose' response works (just like the dose of oranges, not being a truck-size), it's why 'mild stress' is benefitial (only&if) when the system activates these protections (nuclear NRF2/ARE/EpRE translocation, phase II detox, more potent ROS scavenging/quenching/consuming). For example, certain people had atherosclerosis like me and through the years survived/improved things by consuming antioxidants rich meals (mostly in raw veggies/fruits rich in phenols, many turned full/near-vegetarian to save life (as I did/had to)). Blood ORAC/TAC (Oxidant Radical Antioxidant Capacity/Total Antioxidant Capacity) are still good markers and yes, in my case, they were low during my worse periods; and, hence, this contributed to acceleration of the disease. LDL oxidation lag depends on blood ORAC/TAC, if your blood/plasma redox/antioxidative potential of it is low; LDL ox lag will reduce and that will contribute to formation of plaques/ROS/endothelial dysfucntion/destruction.

There was (still, is) lots of ambiguity about ROS.....but one study (though it doesn't mean everything of course) demonstrated that ROS really do rise/accumulate with age; this was verified from 20 to a 100 years old in humans mitos. It's not something inconsequential, for sure...yes, we have ROS, and yes you can function with them - you need them for function/signaling - but, again, 'too much of a good thing is just as bad as too little'. There is a fine line with ROS - very fine line, micro/nano-fine line, it's that finnicky. That's the balance between antioxidative and oxidative systems; with age the former is not capable of balacing out the latter; and, these last ones, take over and that is what we see, evelation of ROS in mitochondrias - Not just 'statying stagnant/frozen levels of ROS' - with the years and, this, actually, also correlates to the results in the redox (the redox will become oxidized (or should I say, it will become 'impossible to quench/consume 'enough' the ROS anymore; depleted of antioxidation/thiols) which will cause constant chronic inflammation activation/DDR/Telomeric damage signal, this in turn will lead to chromosomal dysfunction/ mPTP/apoptosis/ senescence/DNA frags/methylation loss (leading to 'derepression' of inflammation/activation of it - being Young keeps you 'silenced' on the inflammasome, because you don'T want it activated; with age, it activates), and, on the clock (epiclock) you will advance at some point (epiclock is special and not always related to 'straight' damages..but yes, it reaches that; damages contribute to advancement, even on the epigenomic clock (albeit, it is different as shown in certain studies, the episignature is oftenly that of someone 'diseased' not necesarilly 'older'/there's a epidistinction between a Young person of 20 years old dying of CVD vs a 'healthy' elder of 93 years old, still going (i.e. the Young person is younger on the clock but shows 'disturbed patterns' - which are clear signs of 'premature disease'...while the old person has the 'regular program' going...she/he has accumulated lots of 'aging tabs' on clock...but the homeostasis/health is kept...so they keep on going..but soon, it will be over - the MSLP (Maximum Lifespan Potential) the clock, in that elder person, shows clear 'emptying' of the cytosine/DNA content/thus global demethylation is much higher in the elder and they acquired a zillion 'new combinations/variations/mutations' on their clock -which don't help for stability) - and the clock, itself - also contributes to damage accrual speeding up (it is not just innocuous 'time tabs', these tabs 'once reached/recorded' (like checkpoints) lead to a 'self'-orchestration' 'The (epi)Program of Aging' - thousands upon thousands of genes activation/silencing, in DNA, vice versa)).

Posted by: CANanonymity at August 29th, 2019 11:31 PM

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